Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Department of Trauma Surgery, University of Erlangen-Nuremberg, Erlangen, Germany.
Ann Rheum Dis. 2016 May;75(5):883-90. doi: 10.1136/annrheumdis-2014-207109. Epub 2015 Apr 9.
Nintedanib is a tyrosine kinase inhibitor that has recently been shown to slow disease progression in idiopathic pulmonary fibrosis in two replicate phase III clinical trials. The aim of this study was to analyse the antifibrotic effects of nintedanib in preclinical models of systemic sclerosis (SSc) and to provide a scientific background for clinical trials in SSc.
The effects of nintedanib on migration, proliferation, myofibroblast differentiation and release of extracellular matrix of dermal fibroblasts were analysed by microtitre tetrazolium and scratch assays, stress fibre staining, qPCR and SirCol assays. The antifibrotic effects of nintedanib were evaluated in bleomycin-induced skin fibrosis, in a murine sclerodermatous chronic graft-versus-host disease model and in tight-skin-1 mice.
Nintedanib dose-dependently reduced platelet-derived growth factor-induced and transforming growth factor-β-induced proliferation and migration as well as myofibroblast differentiation and collagen release of dermal fibroblasts from patients with and healthy individuals. Nintedanib also inhibited the endogenous activation of SSc fibroblasts. Nintedanib prevented bleomycin-induced skin fibrosis in a dose-dependent manner and was also effective in the treatment of established fibrosis. Moreover, treatment with nintedanib ameliorated fibrosis in the chronic graft-versus-host disease model and in tight-skin-1 mice in well-tolerated doses.
We demonstrate that nintedanib effectively inhibits the endogenous as well as cytokine-induced activation of SSc fibroblasts and exerts potent antifibrotic effects in different complementary mouse models of SSc. These data have direct translational implications for clinical trials with nintedanib in SSc.
尼达尼布是一种酪氨酸激酶抑制剂，最近两项复制的 III 期临床试验表明其可延缓特发性肺纤维化的疾病进展。本研究旨在分析尼达尼布在系统性硬化症（SSc）的临床前模型中的抗纤维化作用，并为 SSc 的临床试验提供科学依据。
通过微量四唑盐和划痕试验、应激纤维染色、qPCR 和 SirCol 试验分析尼达尼布对真皮成纤维细胞迁移、增殖、肌成纤维细胞分化和细胞外基质释放的影响。在博来霉素诱导的皮肤纤维化、小鼠硬皮病慢性移植物抗宿主病模型和 Tsk/+小鼠中评估尼达尼布的抗纤维化作用。
尼达尼布剂量依赖性地降低血小板衍生生长因子诱导和转化生长因子-β诱导的增殖和迁移以及真皮成纤维细胞的肌成纤维细胞分化和胶原释放，无论是来自患者还是健康个体的成纤维细胞。尼达尼布还抑制 SSc 成纤维细胞的内源性激活。尼达尼布以剂量依赖性方式预防博来霉素诱导的皮肤纤维化，并且对已建立的纤维化也有效。此外，尼达尼布治疗可改善慢性移植物抗宿主病模型和 Tsk/+小鼠的纤维化，且在可耐受剂量下。
我们证明尼达尼布可有效抑制 SSc 成纤维细胞的内源性和细胞因子诱导的激活，并在不同的 SSc 互补小鼠模型中发挥强大的抗纤维化作用。这些数据对 SSc 中尼达尼布的临床试验具有直接的转化意义。
